Correlation of Twist upregulation and senescence bypass during the progression and metastasis of cervical cancer

Abstract

Cervical carcinoma is associated with high propensity for local invasion and lymph node metastasis. However, the molecular alterations that drive progression and metastasis of cervical cancer remain unclear. Cellular senescence has been proposed as the mechanism that protects an organism against cancer progression and metastasis. In addition, Twist, a basic helix-loop-helix transcription factor, has been suggested as an oncogene because it is overexpressed in many types of human cancer. This gene also exhibits a positive function in regulating invasion and metastasis. In this study, Twist was strongly and positively expressed in normal tissue, squamous cell carcinoma (SCC) IA--IIA, and SCC IIB--IIIB (4.3%, 44%, and 88.9%, respectively). The strong positive expressions of the senescence marker CBX3 were 39.1%, 32%, and 15.6%, respectively. The strong positive expressions of Twist in the SCC groups with or without lymph node metastasis were 80.8% and 50%. For CBX3, such expressions were 7.7% and 29.5%, respectively. Results also showed that the expression of Twist was inversely correlated with that of CBX3. Moreover, the knockdown of Twist with target siRNA in SiHa triggered the induction of the chromatin marker of the cellular senescence CBX3 and senescence-associated β-galactosidase activity. Our results suggested that the expression of Twist increased during the progression and metastasis of cervical cancer. Furthermore, Twist-induced senescence bypass is important in this process.

Keywords

cervical cancer / senescence / Twist / CBX3 / lymph node metastasis

References

[1] zur Hausen H. Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer2002; 2(5): 342-350

[2] Ozalp S, Yalcin OT, Oner U, Tanir HM, Acikalin M, Sarac I. Microvessel density as a prognostic factor in preinvasive and invasive cervical lesions. Eur J Gynaecol Oncol2003; 24(5): 425-428

[3] Rodier F, Campisi J. Four faces of cellular senescence. J Cell Biol2011; 192(4): 547-556

[4] Bartkova J, Rezaei N, Liontos M, Karakaidos P, Kletsas D, Issaeva N, Vassiliou LV, Kolettas E, Niforou K, Zoumpourlis VC, Takaoka M, Nakagawa H, Tort F, Fugger K, Johansson F, Sehested M, Andersen CL, Dyrskjot L, Ørntoft T, Lukas J, Kittas C, Helleday T, Halazonetis TD, Bartek J, Gorgoulis VG. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature2006; 444(7119): 633-637

[5] Huang Y, Myers MP, Xu RM. Crystal structure of the HP1-EMSY complex reveals an unusual mode of HP1 binding. Structure2006; 14(4): 703-712

[6] Tiwari N, Gheldof A, Tatari M, Christofori G. EMT as the ultimate survival mechanism of cancer cells. Semin Cancer Biol2012; 22(3): 194-207

[7] Prieur A, Peeper DS. Cellular senescence in vivo: a barrier to tumorigenesis. Curr Opin Cell Biol2008; 20(2): 150-155

[8] Smit MA, Peeper DS. Epithelial-mesenchymal transition and senescence: two cancer-related processes are crossing paths. Aging (Albany NY)2010; 2(10): 735-741

[9] Qin Q, Xu Y, He T, Qin C, Xu J. Normal and disease-related biological functions of Twist1 and underlying molecular mechanisms. Cell Res2012; 22(1): 90-106

[10] Ansieau S, Bastid J, Doreau A, Morel AP, Bouchet BP, Thomas C, Fauvet F, Puisieux I, Doglioni C, Piccinin S, Maestro R, Voeltzel T, Selmi A, Valsesia-Wittmann S, Caron de Fromentel C, Puisieux A. Induction of EMT by twist proteins as a collateral effect of tumor-promoting inactivation of premature senescence. Cancer Cell2008; 14(1): 79-89

[11] Kwok WK, Ling MT, Yuen HF, Wong YC, Wang X. Role of p14ARF in TWIST-mediated senescence in prostate epithelial cells. Carcinogenesis2007; 28(12): 2467-2475

[12] Li Y, Wang W, Wang W, Yang R, Wang T, Su T, Weng D, Tao T, Li W, Ma D, Wang S. Correlation of TWIST2 up-regulation and epithelial-mesenchymal transition during tumorigenesis and progression of cervical carcinoma. Gynecol Oncol2012; 124(1): 112-118

[13] Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: Globocan 2000. Int J Cancer2001; 94(2): 153-156

[14] Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin2011; 61(2): 69-90

[15] Tiwari N, Gheldof A, Tatari M, Christofori G. EMT as the ultimate survival mechanism of cancer cells. Semin Cancer Biol2012; 22(3): 194-207

[16] Chandeck C, Mooi WJ. Oncogene-induced cellular senescence. Adv Anat Pathol2010; 17(1): 42-48

[17] Foroni C, Broggini M, Generali D, Damia G. Epithelial-mesenchymal transition and breast cancer: role, molecular mechanisms and clinical impact. Cancer Treat Rev2012; 38(6): 689-697

[18] Cheng GZ, Chan J, Wang Q, Zhang W, Sun CD, Wang LH. Twist transcriptionally up-regulates AKT2 in breast cancer cells leading to increased migration, invasion, and resistance to paclitaxel. Cancer Res2007; 67(5): 1979-1987

[19] Lee TK, Poon RT, Yuen AP, Ling MT, Kwok WK, Wang XH, Wong YC, Guan XY, Man K, Chau KL, Fan ST. Twist overexpression correlates with hepatocellular carcinoma metastasis through induction of epithelial-mesenchymal transition. Clin Cancer Res2006; 12(18): 5369-5376

[20] Lee KW, Kim JH, Han S, Sung CO, Do IG, Ko YH, Um SH, Kim SH. Twist1 is an independent prognostic factor of esophageal squamous cell carcinoma and associated with its epithelial-mesenchymal transition. Ann Surg Oncol2012; 19(1): 326-335

[21] Kajiyama H, Shibata K, Umezu T, Mizuno M, Suzuki S, Yamamoto E, Fujiwara S, Kikkawa F. Expression of Twist enhances risk of poor oncologic outcome in patients with stage Ib to II cervical carcinoma with lymphovascular space involvement. Hum Pathol2013; 44(2): 181-188

[22] Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell2009; 139(5): 871-890

[23] Pedraza-Fariña LG. Mechanisms of oncogenic cooperation in cancer initiation and metastasis. Yale J Biol Med2006; 79(3-4): 95-103

Acknowledgements

This study was financially supported by the National Natural Science Foundation of China (Grant No. 81071663).

Compliance with ethics guidelines

Tian Wang, Yan Li, Abidan Tuerhanjiang, Wenwen Wang, Zhangying Wu, Ming Yuan, and Shixuan Wang declare that they have no conflict of interest. All of the procedures followed in this study were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and the Helsinki Declaration of 1975 revised in 2000 (5). Informed consent was obtained from all of the patients included in this study.

RIGHTS & PERMISSIONS

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg